Epithelial cells (ECs), dendritic cells (DCs), and T cells (effector and regulatory T cells, Tregs) orchestrate oral immunity. Oral immune function is perturbed during HIV infection resulting in the increased susceptibility to infection with organisms that would normally be controlled (e.g., oropharyngeal candidiasis). Not only are cells functionally modified as a result of infection, Treg numbers increase in the tonsils (not blood) and DC numbers decrease with disease progression. Impaired DC function coincident with elevated Treg activity might facilitate (at least some of) this reduced effector immunity. Treating people with antiretroviral therapies (ART) should control virus amplification to limit immune destruction, but also must not interfere with (and, if possible, improve) oral immune function. Therefore, DCs and T cells (and ECs) within the outer epithelial layers as well as the mucosal associated lymphoid tissues of the oral cavity need to be studied closely during ART. Combined PMPA/FTC ART controls SIV growth in macaques providing an excellent system to study the possible side effects that ART may impart on oral immune function. ART treatment of SIV-infected animals will restrict virus growth and impede the virus-induced immune destruction. We will also examine uninfected animals treated or not with ART, to dissect direct effects of ART vs those driven by the initiation of infection and persistent low-level virus replication in ART-treated infected animals. Such controlled, comparative studies are unable to be made in humans, stressing the need for these sorts of animal studies. We hypothesize that ART will not significantly alter innate and adaptive oral (or distal) immune activities in infected and uninfected animals, while classical immune dysfunction will be observed in the infected animals not receiving ART. This will be explored in three aims: (i) To evaluate the effect of continuous ART on innate and adaptive oral mucosal responses, (ii) To assess if ART impacts the ability of animals to respond to and/or control oral Candida, and (iii) To determine whether poly(IC) can boost oral immunity in ART-treated animals. The basic effects of ART will be revealed in Aim 1 and these animals will be used to gain more extensive insight into oral immune function in aims 2 and 3. In the latter aims we will examine the responses to Candida albicans challenge as well as the potent DC and EC stimulus poly(IC). Healthy oral cavities are expected to respond to and control Candida. They should also respond strongly to poly(IC) by boosting immune functions to help maintain virus control upon cessation of ART. Immunity will be manifest as strong cytokine and chemokine responses, DC activation, limited Treg activation/expansion, and solid effector T cell responses. This will reveal important details about oral immune function, as well as advancing strategies to boost oral immunity to augment ART.